Infectious keratitis (IK) is a significant global health problem, affecting millions annually, and it can lead to blindness if not treated promptly1,2 — the World Health Organization calls it a silent epidemic.3 Early intervention is crucial during the initial microbial invasion before stromal involvement, as this represents a window of opportunity to treat without serious visual sequelae.3,4 Once the stroma is involved, ulceration occurs, and this ultimately leads to corneal scarring. Unfortunately, IK is often diagnosed for the first time after this point. The infection can be caused by bacteria, fungi, viruses, or parasites like Acanthamoeba, and the infection can spread rapidly.5 This means that the rapid determination of the causative pathogen is important, as this determines the antimicrobial therapies chosen to treat the infection.
Although confocal microscopy can help with this process, not all centers have access to this technique and as such, may have to rely on the results of corneal scrape cultures, which can take up to 1-2 days to yield a result — assuming the samples are successfully cultured.5 Although experienced corneal specialists will likely be able to identify the causative pathogens accurately most of the time, any incorrect identifications can lead to the administration of the wrong therapy. This risks the infection spreading further — after all, antibiotics do little to kill fungi, and antifungals don’t make great antibiotics.
Additionally, traditional antimicrobial drug treatment is time-consuming and expensive. For example, bacterial keratitis treatment requires the hourly administration of fortified antibiotics.6 Antifungal treatment can be even more intensive, potentially involving systemic and topical agents applied every 30 minutes initially, then hourly thereafter. This approach is highly time-consuming and resource-intensive, and this has a large impact on the treatment’s cost. In Australia, the average treatment cost of bacterial ulcers was AU$1,400, and the cost for fungal ulcer treatment was AU$4,600.7,8 In addition, all antimicrobials may not be available in all countries, and sometimes patients may not be able to afford these costs, leading to untreated infections and with a significant societal and economic impacts.
Compounding these problems is the issue of antimicrobial resistance: many of the antimicrobial drugs we rely on today may not remain effective in the future. There is a need for an alternative method of treating IK, and that need becomes more urgent every day.
Cross-Linking Corneal Infections
Readers of Corneal Physician will doubtlessly be aware of corneal cross-linking (CXL) for the treatment of corneal ectasias.9 You will already know that it involves the saturation of the stroma with riboflavin, which is followed by UV irradiation, and that the photochemical reaction between the UV and riboflavin generates reactive oxygen species (ROS), which cross-link together stromal collagen and proteoglycan molecules and by doing so, strengthens the cornea, treating the ectasia.10 But these ROS have other effects (Figure 1), and that includes directly causing damage to the cell membranes and nucleic acids of any pathogens present, which can, respectively, lyse the pathogen, and inhibit pathogen replication.11
Another side-effect of CXL-induced binding of stromal molecules is that this process also hides protease binding sites, making it harder for pathogen-produced proteases to digest the stroma.12 This means that the size of the ulcer — and therefore the eventual corneal scar size — becomes constrained.13 Furthermore, the mechanism of CXL’s pathogen-killing effect is entirely independent of how antimicrobial drugs work, so pathogens resistant to these drugs should still be susceptible to cross-linking.
In CXL for ectasia, the amount of UV energy delivered to the cornea has historically been limited to 5.4 J/cm², in large part to create a safety margin of untreated cornea to protect the corneal endothelium from UV-related damage.14 Although there is now evidence that somewhat higher UV fluences, up to ~10 J/cm², can be used to safely cross-link ectatic corneas,15 it is clear that CXL to treat IK should deploy higher-fluence irradiation protocols.16-22 There is a simple reason for this: infections and corneal ulcers are opaque and absorb UV energy, meaning that higher fluences can deliver a greater killing effect without risking corneal endothelial cell decompensation (Figure 2).
It is worth noting that the combination of riboflavin and UV energy is not the only one: rose bengal/532 nm green light CXL is also used to treat IK.19,23-25 For this reason, the terminology used to describe the use of CXL to treat IK does not specify a particular chromophore. In this context, it is called photoactivated chromophore for keratitis–corneal cross-linking (PACK-CXL).
Clinical Evidence and Case Studies
The first use of CXL for infections was in 2008, with promising results.26 Recent studies, including a systematic review and meta-analysis by Ting et al, showed that adjuvant PACK-CXL significantly shortens healing time compared to standard antimicrobial therapy.27 Makdoumi et al also demonstrated the potential of PACK-CXL as a first-line monotherapy for bacterial keratitis, achieving epithelial healing in all cases with minimal need for additional antibiotics.28
A recent Phase 3 trial validated PACK-CXL’s efficacy at treating bacterial, fungal, and mixed bacterial/fungal-origin IK.29 The results of the trials showed comparable healing rates between PACK-CXL and standard antimicrobial treatments,30 with PACK-CXL achieving 89% success without additional therapy. This is important: it suggests that in the majority of cases, PACK-CXL may be used as a “one-and-done” therapy. In Switzerland, we would always follow the patient closely and also administer antimicrobial therapy in case the therapy fails, but it in some LMICs, the situation may be different. Agricultural workers from rural areas, even if they can afford to travel to an urban center with a hospital where treatment is available, may only have enough money for one consultation. Even if these patients do leave the consultation with antimicrobial therapies, they may not be able to return for a second appointment for cost reasons. Many patients are lost — and if the keratitis progresses, so may be their vision. If PACK-CXL successfully treats many of these patients in a one-and-done fashion, then the risk of patients falling through this gap becomes smaller, and fewer people will lose vision to IK.
We now have laboratory evidence that high fluence PACK-CXL is highly effective against several bacterial and fungal strains,19 and we have successfully used combined, sequential PACK-CXL protocols of both UV and riboflavin, and rose bengal and green light to treat a case of acanthamoeba keratitis.31 PACK-CXL, therefore, appears to be an extremely attractive treatment option for IK, ideally as an adjunct to conventional therapies. In situations where these are not available however, it may act as an effective standalone therapy too.
Slit lamp PACK-CXL
CXL for ectasia can be performed at the slit lamp in a doctor’s office as easily and as safely as CXL performed in a sterile operating room (OR), as, after all, the cornea is effectively sterilized at the end of the procedure.32 Any postsurgical infection risks are associated with how the cornea is handled after the procedure — and this applies equally to both settings.
The office-based slit lamp setting (Figure 3) has several advantages over and above the cost and resource savings of leaving the OR.32 In the case of IK, bringing an infected eye into the OR for treatment is never ideal, especially at the start, rather than the end of the day, so here, PACK-CXL at the slit lamp makes additional sense.32
Although the cost savings and flexibility in timing and location are welcome in any setting, the advantages of PACK-CXL at the slit lamp are particularly valuable in LMICs. The slit lamp is nearly ubiquitous: if eye care is being administered, you can virtually guarantee a slit lamp is available — even if it is a field hospital or a rural health center. With the advent of portable, battery-powered, slit-mountable cross-linking devices, PACK-CXL can be brought to even the most rural of LMIC locations and deployed to treat IK and save sight.
Conclusion
Although IK is a severe global health issue, as is the increase in antimicrobial-resistant pathogens, PACK-CXL is a method that can address these issues. The technique is pathogen-agnostic: it kills pathogens irrespective of phylum, and it can be performed almost immediately on the presentation of a patient with IK, mitigating the worries about delayed identification of the causative pathogen and the potential use of the wrong class of drug in the meantime. Bringing PACK-CXL to the slit lamp with a portable cross-linking device reduces costs and resourcing issues and enables the technique to be brought to far more people than was possible with older-generation cross-linking devices, especially those in LMICs.
Finally, its ability in many cases to be a “one-and-done” procedure may provide treatment benefits to doctors and patients alike in decreasing the need for multiple follow-up visits. However, it is still strongly cautioned that patients should be followed up till evidence of complete healing is confirmed. Thus, possible advantages of PACK-CXL are beneficial to all countries, but their impact will be most felt in LMICs, where IK is more prevalent and its outcomes worse. Lowering these costs and access barriers to treatment democratizes PACK-CXL by bringing it to more people who need it. CP
References
1. Thylefors B. Epidemiological patterns of ocular trauma. Aust N Z J Ophthalmol. 1992;20(2):95-98.
2. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79(3):214-221.
3. Whitcher JP, Srinivasan M. Corneal ulceration in the developing world--a silent epidemic. Br J Ophthalmol. 1997;81(8):622-623.
4. Srinivasan M, Gonzales CA, George C, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India. Br J Ophthalmol. 1997;81(11):965-971.
5. Upadhyay MP, Karmacharya PC, Koirala S, et al. Epidemiologic characteristics, predisposing factors, and etiologic diagnosis of corneal ulceration in Nepal. Am J Ophthalmol. 1991;111(1):92-99.
6. Lin A, Rhee MK, Akpek EK, et al; American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Bacterial keratitis preferred practice pattern. Ophthalmology. 2019;126(1):P1-P55.
7. Keay L, Edwards K, Naduvilath T, et al. Microbial keratitis predisposing factors and morbidity. Ophthalmology. 2006;113(1):109-116.
8. Wong T, Ormonde S, Gamble G, McGhee CN. Severe infective keratitis leading to hospital admission in New Zealand. Br J Ophthalmol. 2003;87(9):1103-1108.
9. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620-627.
10. Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf. 2013;11(2):65-74.
11. Tabibian D, Mazzotta C, Hafezi F. PACK-CXL: corneal cross-linking in infectious keratitis. Eye Vis (Lond). 2016;3:11.
12. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res. 2004;29(1):35-40.
13. Achiron A, Elhaddad O, Regev T, et al. PACK cross-linking as adjuvant therapy improves clinical outcomes in culture-confirmed bacterial keratitis. Cornea. 2022;41(9):1069-1073.
14. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea. 2007;26(4):385-389.
15. Seiler TG, Batista A, Frueh BE, Koenig K. Riboflavin concentrations at the endothelium during corneal cross-linking in humans. Invest Ophthalmol Vis Sci. 2019;60(6):2140-2145.
16. Awad R, Hafezi F, Ghaith AA, et al. Comparison between three different high fluence UVA levels in corneal collagen cross-linking for treatment of experimentally induced fungal keratitis in rabbits. Eur J Ophthalmol. 2022;32(4):1907-1914.
17. Hafezi F, Munzinger A, Goldblum D, Hillen M, Tandogan T. Repeated high-fluence accelerated slitlamp-based photoactivated chromophore for keratitis corneal cross-linking for treatment-resistant fungal keratitis. Cornea. 2022;41(8):1058-1061.
18. Kling S, Hufschmid FS, Torres-Netto EA, et al. High fluence increases the antibacterial efficacy of PACK cross-linking. Cornea. 2020;39(8):1020-1026.
19. Lu NJ, Koliwer-Brandl H, Hillen M, Egli A, Hafezi F. High-fluence accelerated PACK-CXL for bacterial keratitis using riboflavin/UV-A or rose Bengal/green in the ex vivo porcine cornea. Transl Vis Sci Technol. 2023;12(9):14.
20. Nateghi Pettersson M, Lagali N, Mortensen J, Jofre V, Fagerholm P. High fluence PACK-CXL as adjuvant treatment for advanced Acanthamoeba keratitis. Am J Ophthalmol Case Rep. 2019;15:100499.
21. Olshaker H, Achiron A, Chorny A, et al. Accelerated high fluence photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL) at the slit lamp: a pilot study. Front Pharmacol. 2023;14:1229095.
22. Richoz O, Kling S, Hoogewoud F, et al. Antibacterial efficacy of accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking (PACK-CXL). J Refract Surg. 2014;30(12):850-854.
23. Altamirano D, Martinez J, Leviste KD, Parel JM, Amescua G. Photodynamic therapy for infectious keratitis. Curr Ophthalmol Rep. 2020;8:245-251.
24. Amescua G, Arboleda A, Nikpoor N, et al. Rose Bengal photodynamic antimicrobial therapy: a novel treatment for resistant fusarium keratitis. Cornea. 2017;36(9):1141-1144.
25. Naranjo A, Arboleda A, Martinez JD, et al. Rose Bengal photodynamic antimicrobial therapy for patients with progressive infectious keratitis: a pilot clinical study. Am J Ophthalmol. 2019;208:387-396.
26. Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008;27(5):590-594.
27. Ting DSJ, Henein C, Said DG, Dua HS. Photoactivated chromophore for infectious keratitis - Corneal cross-linking (PACK-CXL): A systematic review and meta-analysis. Ocul Surf. 2019;17(4):624-634.
28. Makdoumi K, Mortensen J, Sorkhabi O, Malmvall BE, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012;250(1):95-102.
29. Hafezi F, Hosny M, Shetty R, et al. PACK-CXL vs. antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022;9(1):2.
30. Saidel MA. Acanthamoeba keratitis treatment. Published April 1, 2006. Accessed July 31, 2024. https://www.aao.org/education/current-insight/acanthamoeba-keratitis-treatment.
31. Hafezi F, Messerli J, Torres-Netto EA, et al. Successfully combining riboflavin/UV-A and rose bengal/green light PACK cross-linking in Acanthamoeba keratitis. Paper presented at: Annual meeting of the European Society of Cataract and Refractive Surgeons; Sept. 8-12, 2023; Vienna.
32. Hafezi F, Richoz O, Torres-Netto EA, Hillen M, Hafezi NL. Corneal cross-linking at the slit lamp. J Refract Surg. 2021;37(2):78-82.
